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Hailey Howard

on 1 March 2014

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Transcript of Tamoxifen

Tamoxifen, chemically known as (Z)-2-[4-(1,2-diphenylbut-1-enyl)phenoxy]-N,N-dimethylethanamine, is a SERM (selective estrogen receptor modulator).[20] Tamoxifen acts as an agonist in tissues such as bone marrow and endometrial cells or as an antagonist in breast tissue.[10] Pharmcologically it acts on the estrogen receptor via the cytochrome P450 gene in the liver, although only in tissues where it works agonistically, decreasing DNA synthesis of estrogen.[9] Antagonistically it binds to the estrogen receptor, producing anti-estrogenic effects. Its metabolized via the CYPD26 gene.[8][15] Its labeled as several different brand names all over the world. Majorly used clinically to treat breast cancer, among other illness such as: McCune Albright Syndrome, infertility, depression, etc. It is only available orally, and common adult dosage is 20-40 mg twice a day. Clinical contraindications would be absence of gene CYPD26, if one has access and resources to do a gene profile. However major clinical contraindications include hypersensitivity to warfarin, deep vein thrombosis and pulmonary embolisms. Major unwanted effects include: uterine cancer, pulmonary embolism and strokes via clotting mechanisms. Minor unwanted effects include: nausea, vomiting, hot flashes,etc.[17] Alternative therapies include mastectomies, gene slicing (not recommended), or other drugs for instance: fulvestrant [17] or aromatase inhibitors [17].

Fun fact: Men are capable of developing breast cancer as well. They do have breast tissue,
although not as developed as women. Factors such as alcoholism, obesity,
Klinefelter syndrome, and testicle problems can lead to increased risk of breast cancer.[25]

Fun fact: Aside from Angelina Jolie, who made headlines regarding her double mastectomy, other celebrities such as Christina Applegate, Giuliana Rancic, Kathy Bates, and Wanda Sykes have made the decision to surgically remove their breasts to lower the chance of being diagnosed with breast cancer. [25]

Breast cancer is the leading type of cancer in women. According to the Canadian Breast Cancer Foundation, 1 in 9 women in Canada will be diagnosed with breast cancer in their life time. [3] Approximately 23,800 women and 200 men in Canada were affected in 2013. [3]

Breast tissue covers a large area of the chest, extending up to the collarbone, from the armpits across to the breastbone. Each breast is made up of glands, ducts, and fatty tissue. Lobules are grouping of glands that make milk for breastfeeding and fatty tissue acts as the cushion and protects the lobules and ducts. [25]

Cancerous cells generally start within the ducts and or the lobules of the breasts; ductal carcinoma is the most common type of breast cancer.[25] It can spread to other areas beyond the breast if the cancerous cells break off from the tumor and travel through the bloodstream or lymphatic system (breast cancer metastasis).[25]

Presently, there is no specific cause of breast cancer, it is believed that a combination of genetics (BRCA gene mutation) and the environment plays a part in the development of breast cancer.
There are several ways of treating breast cancer, it depends on the type and stage of cancer as well as the patient. There are the common ones such as mastectomy, and its opposite, breast-conserving surgery, radiation and chemotherapy.[25] There is also biological and the topic of this presentation—hormonal therapy.[25] It is generally used for hormone receptor-positive breast cancer, in the early stages, locally advanced, advanced or recurrent.[4] The focus of this presentation is TAMOXIFEN, an antagonist of the estrogen receptor, as it is estrogen that allows the growth of certain breast cancers.[4] It can also be used as a preventative treatment for those who have high risk for breast cancer. [4]

Mechanism of Action
The MOA of Tamoxifen is complex
Tamoxifen can be either estrogenic (eg in uterine epithelium) or antiestrogenic (eg in mamory epithelium) in action depending on the tissues that it is acting upon. [10]
Principle MOA is through the binding of estrogen receptors which blocks the proliferative action on estrogen
The antiestrogenic mechanism is thought to be achieved through the induction of the synthesis of TGF-beta, which is a cytokine transforming growth factor that acts as a negative regulatory molecule
These antiestrogenic effects may also be seen in cells lacking estrogen-receptors
The antiestrogenic mechanism acts both in paracrine (neighboring cells) and autocrine (self) fashions [10]
Tamoxifen can lower the concentration of IGF-I (insulin-like growth factor I) in breast cancer patients
IGF-I has been found to be a potent mitogen for breast cancer cells which can act through endocrine, paracrine or autocrine action to stimulate growth [9]
Adult Dosages
Breast Cancer - Metastatic
20 - 40mg/day PO
same dosing for males and females
divide dose to BID if more than 20mg/day
Breast Cancer - Adjuvant Therapy
20 - 40mg/day PO for 5 yrs
use following total/partial mastectomy, axillary dissection, and breast external beam radiation, and to decrease cancer risk in contralateral breast
Ductal Cancer - Localized
20mg/day PO for 5 yrs
Following breast surgery , external beam radiation and decrease invasive breast cancer risk
Breast Cancer Prevention
20mg/day PO for 5 yrs
For high risk women
Mastalgia (breast pain)
10mg/day PO for 4 months
Ovulation Induction
5 - 40mg/day PO BID for 4 days
Renal Dosing
No adjustment
Hepatic Dosing
Not defined
Pediatric Dosages
McCune-Albright Syndrome
20mg/day PO
for 2 - 10 yrs old
Renal Dosing
Same as adult
If renal impairment present then dose adjustment may be necessary although pediatric dosing adjustments not defined
Hepatic Dosing
not defined
Hypersensitivity to; drug, class of drugs, components of drug
Undiagnosed vaginal bleeding
Thromboembolism history (issue for breast cancer prevention or ductal cancer in situ)
Coumarin anticoagulation (issue for ductal cancer in situ)
Caution if thromboembolism (issue for cancer therapy)
Caution if coumarin anticoagulation (issue for cancer therapy)
Caution if bone metastases
Caution if thrombocytopenia
Caution if leukopenia
Caution if poor CYP2D6 metabolizer
Not recommended while breast feeding
Common Reactions
hot flashes
vaginal discharge
menstrual irregularities
vaginal bleeding
disease flare, transient
bone or tumor pain increase

peripheral edema
visual acuity changes
vaginal dryness
vulvar pruritus
hair thinning/loss
thrombocytopenia, transient
LFTs elevated

Serious Reactions
endometrial hyperplasia/polyps
endometrial CA

uterine sarcoma
uterine fibroids
ovarian cysts
hepatic CA
erythema multiforme
hypersensitivity rxn
Alternative Treatments
IVF (in vitro fertilization)
Clomiphene citrate (seraphene and clomid)
Human menopausal gonadotropin (pregonal, humegon and repronex)
Follicle stimulating hormone
Breast Cancer
Mastectomy (total or partial)
Ductal Cancer - Insitu
McCune-Albright Syndrome
Testolactone and other drugs which block the synthesis of estrogen
Clinical Indications
Angiogenesis and cancer
McCune-Albright syndrome
Generic names
Brand names
Tamoxifen is widely available around the world with a prescription.

In the US, 600mg of tamoxifen costs $45 (60, 10mg tablets) or $146 (30, 20mg tablets)
Bipolar disorder
Control of gene expression
Synthesis of estrogen
Riedel's thyroiditis
Group 4
Hailey Howard, Josh Blasco, Jennifer Liu, Christy Hui, Amber Geissler, Kelsey Martell
MOA Continued
Tamoxifen is a pro-drug which requires metabolization by a CYP enzyme in order to become metabolically active.
CYP 2D6, CYP 3A, CYO 2B6
produce the active metabolites; 4-hydroxytamoxifen and N-desmethyl-4- hydroxytamoxifen
30-100 times higher binding affinity for the estrogen receptor than tamoxifen [8], [15]
Perillyl alcohol and methyl jasminate are plant extracts
Cisplatin is currently used as a chemotherapy drug but is limited by its toxicity to the patient.
Both perillyl alcohol and methyl jasminate have antitumor properties against breast cancer
Methyl jasminate activated tumor necrosis factor receptor 1 in prostate and breast cancer cells, and decreased membrane potential in breast cancer cells
Cisplatin is reported to release tumor necrosis factor alpha.
When they are combined with cisplatin they have a synergistic effect on their anti-cancerous properties (they lower mitochondrial membrane potential and activate Tumor necrosis factor receptor 1).
This effect means that lower doses of cisplatin can be used which is beneficial to the patient

Current Areas of Research
Figure 1: Metabolization of Tamoxifen through various cytochrome p450 enzymes found within the human liver. Metabolization results in five different active forms of the drug. [2] Tamoxifen has a half life of 5-7days, where as its metabolite N-desmethyl tamoxifen has a half life of 14 days, both Tamoxifen and its metabolites are primarily excreted through the feces. [17]
Figure 2: The effects on Tamoxifen on a human cell. Since Tamoxifen is a lipophilic molecule it can easily pass through cell membranes allowing it to act upon different actions of the cell including gene regulation and cytokine actions. For example Tamoxifen has been found to induce cell apoptosis through agonistic modulations on MAPK pathways such as JNK (c-Jun N-terminal kinase) and p38 which signal apoptosis signals due to stress for instance UV or gamma radiation. [11]
Figure 3: Tamoxifen and deoxyribose nucleic acid (DNA) interactions have been found to cause different types of mutations in the DNA sequence by interfering with DNA polymerase's ability to scan the minor groove for base pair mismatches and additions. [22]
1. Blackwell K, Haroon Z, Shan S, Saito W, Broadwater G, Greenberg C, Dewhirst M. Tamoxifen inhibits angiogenesis in estrogen receptor-negative animal models. Clinical cancer research. 2000; 6 (11): 4359--4364.
2. Brown K, Heydon R, Jukes R, White I, Martin E. Further characterization of the DNA adducts formed in rat liver after the administration of tamoxifen, N-desmethyltamoxifen or N, N-didesmethyltamoxifen. Carcinogenesis. 1999; 20 (10): 2011--2016.
3. Cbcf.org. Treatment for Breast Cancer. [Online] Available from: http://www.cbcf.org [Accessed 28 Feb 2014].
4. Dhaliwal L, Suri V, Gupta K, Sahdev S. Tamoxifen: An alternative to clomiphene in women with polycystic ovary syndrome. Journal of human reproductive sciences. 2011; 4 (2): 76.
5. Drugs.com. Tamoxifen - brand name list from Drugs.com. [Online] Available from: http://www.drugs.com/ingredient/tamoxifen.html [Accessed 28 Feb 2014].
6. Eugster E, Rubin S, Reiter E, Plourde P, Jou H, Pescovitz O. Tamoxifen treatment for precocious puberty in McCune-Albright syndrome: a multicenter trial. The Journal of pediatrics. 2003; 143 (1): 60--66.
7. Few J, Thompson N, Angelos P, Simeone D, Giordano T, Reeve T. Riedel's thyroiditis: treatment with tamoxifen. Surgery. 1996; 120 (6): 993--999.
8. Fleeman N, Martin Saborido C, Payne K, Bol, Dickson R, Dundar Y, Fern', Ez-Sant, Er A, Howell S, Newman W, Oyee J, Others. The clinical effectiveness and cost-effectiveness of genotyping for CYP2D6 for the management of women with breast cancer treated with tamoxifen: a systematic review. 2011;.
9. Healthlinkbc.ca. Tamoxifen. [Online] Available from: http://www.healthlinkbc.ca/kb/content/drugdetail/tv5307.html [Accessed 28 Feb 2014].
10. Kufe D, Pollock R, Weichselbaum R, Bast R, Gansler T, Holl, Frei E, Sporn M, Lippman S, Others. Agents for Chemoprevention and Their Mechanism of Action. BC Decker. 2003;.
11. M, Lekar S, Hebbar V, Christov K, Kong A. Pharmacodynamics of tamoxifen and its 4-hydroxy and N-desmethyl metabolites: activation of caspases and induction of apoptosis in rat mammary tumors and in human breast cancer cell lines. Cancer research. 2000; 60 (23): 6601--6606.
12. Maughan K, Lutterbie M, HAM P. Treatment of breast cancer.. American family physician. 2010; 81 (11).
13. Mayoclinic.org. Ductal carcinoma in situ (DCIS) Treatment at Mayo Clinic - Diseases and Conditions - Mayo Clinic. [Online] Available from: http://www.mayoclinic.org/diseases-conditions/dcis/basics/treatment/con-20031842 [Accessed 27 Feb 2014].
14. Medindia.net. Generic Drug Tamoxifen - List of Brand/ Trade Names | Medindia. [Online] Available from: http://www.medindia.net/drug-price/tamoxifen.htm [Accessed 28 Feb 2014].
15. Nelson H, Fu R, Humphrey L, Smith M, Griffin J, Nygren P. Comparative effectiveness of medications to reduce risk of primary breast cancer in women. Agency for Healthcare Research and Quality (US), Rockville (MD). 2009;.
16. Nlm.nih.gov. McCune-Albright syndrome: MedlinePlus Medical Encyclopedia. [Online] Available from: http://www.nlm.nih.gov/medlineplus/ency/article/001217.htm [Accessed 27 Feb 2014].
17. Online.epocrates.com. tamoxifen Entire Monograph - Epocrates Online. [Online] Available from: https://online.epocrates.com/noFrame/showPage.do?method=drugs&MonographId=287&ActiveSectionId=10 [Accessed 28 Feb 2014].
18. Patient.co.uk. Gynaecomastia | Doctor | Patient.co.uk. [Online] Available from: http://www.patient.co.uk/doctor/Gynaecomastia.htm [Accessed 28 Feb 2014].
19. Pereiras M. Tamoxifen. Oncology Nurse Advisor. 2014;: 41. Available from: http://go.galegroup.com/ps/i.do?id=GALE%7CA237135443&v=2.1&u=ubcolumbia&it=r&p=HRCA&sw=w&asid=11b60edf886635cc288cc3a0a4e0fc63
20. Rcsb.org. RCSB Protein Data Bank - RCSB PDB - 1FJ5 Structure Summary. [Online] Available from: http://www.rcsb.org/pdb/explore/explore.do?structureId=1FJ5 [Accessed 27 Feb 2014].
21. Shi Y, Bassnett S. Inducible gene expression in the lens using tamoxifen and a GFP reporter. Experimental eye research. 2007; 85 (5): 732--737.
22. Shimotakahara S, Gorin A, Kolbanovskiy A, Kettani A, Hingerty B, Amin S, Broyde S, Geacintov N, Patel D. Accomodation of S-cis-Tamoxifen-N2-Guanine Adduct within a Bent and Widened DNA Minor Groove. Journal of molecular biology. 2014; 302 (2): 375-392. [Accessed 26th February 2014].
23. Ucsfhealth.org. Ovulation Induction | Patient Education | UCSF Medical Center. [Online] Available from: http://www.ucsfhealth.org/education/ovulation_induction/ [Accessed 27 Feb 2014].
24. Webmd.com. Tamoxifen May Help Treat Bipolar Mania. [Online] Available from: http://www.webmd.com/bipolar-disorder/news/20080303/tamoxifen-may-help-treat-bipolar-mania [Accessed 28 Feb 2014].
25. www.cancer.ca. Treatment of breast cancer. [Online] Available from: http://www.cancer.ca/en/cancer-information/cancer-type/breast/treatment/?region=bc [Accessed 28 Feb 2014].
26. Zanardi S, Serrano D, Argusti A, Barile M, Puntoni M, Decensi A. Clinical trials with retinoids for breast cancer chemoprevention. Society of Endocrinology. 2006; 13 (1): 51-68. Available from: http://erc.endocrinology-journals.org/content/13/1/51.full.pdf+html [Accessed 28 Feb 2014].

Currently under study
Derived from vitamin A
They prevent cells from becoming tumor cells
They can change malignant cells by activating or repressing some genes.
Both normal and malignant breast tissue cells have retinoid receptors
The mechanism by which retinoids prevent breast cell growth is not completely understood but it is thought that the drug affects gene expression. The drug binds to nuclear receptors that are ligand-activated transcription factors. These regulate cell growth, differentiation and apoptosis.
Fenretinide is the most commonly studied retinoid.
Perilly alcohol, Methyl jasminate
and Cisplatin
Full transcript